Neurobeachin regulates receptor downscaling at GABAergic inhibitory synapses in a protein kinase A-dependent manner

GABAergic synapses critically modulate neuronal excitability, and plastic changes in inhibitory synaptic strength require reversible interactions between GABA_A receptors (GABA_ARs) and their postsynaptic anchor gephyrin. Inhibitory long-term potentiation (LTP) depends on the postsynaptic recruitment of gephyrin and GABA_ARs, whereas the neurotransmitter GABA can induce synaptic removal of GABA_ARs. However, the mechanisms and players underlying plastic adaptation of synaptic strength are incompletely understood. Here we show that neurobeachin (Nbea), a receptor trafficking protein, is a component of inhibitory synapses, interacts with gephyrin and regulates the downscaling of inhibitory synaptic transmission. We found that the recruitment of Nbea to GABAergic synapses is activity-dependent and that Nbea regulates GABA_AR internalization in a protein kinase A (PKA)-dependent manner. In heterozygous neurons lacking one Nbea allele, re-expression of Nbea but not expression of a PKA binding-deficient Nbea mutant rescued the internalization of GABA_ARs. Our data suggest a mechanism by which Nbea mediates PKA anchoring at inhibitory postsynaptic sites to downregulate GABAergic transmission. They emphasize the importance of kinase positioning in the regulation of synaptic strength.